Cellular recovery after prolonged warm ischaemia of the whole body.

After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology3. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.

Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations.

Brain ischemia inhibits immune function systemically, with resulting infectious complications. Whether in stroke different immune alterations occur in brain and periphery and whether analogous mechanisms operate in these compartments remains unclear. Here we show that in patients with ischemic stroke and in mice subjected to middle cerebral artery occlusion, natural killer (NK) cells display remarkably distinct temporal and transcriptome profiles in the brain as compared to the periphery. The activation of catecholaminergic and hypothalamic-pituitary-adrenal axis leads to splenic atrophy and contraction of NK cell numbers in the periphery through a modulated expression of SOCS3, whereas cholinergic innervation-mediated suppression of NK cell responses in the brain involves RUNX3. Importantly, pharmacological or genetic ablation of innervation preserved NK cell function and restrained post-stroke infection. Thus, brain ischemia compromises NK cell-mediated immune defenses through mechanisms that differ in the brain versus the periphery, and targeted inhibition of neurogenic innervation limits post-stroke infection.

Diffusion-Weighted Imaging Fluid-Attenuated Inversion Recovery Mismatch on Portable, Low-Field Magnetic Resonance Imaging Among Acute Stroke Patients.

OBJECTIVE: For stroke patients with unknown time of onset, mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) can guide thrombolytic intervention. However, access to MRI for hyperacute stroke is limited. Here, we sought to evaluate whether a portable, low-field (LF)-MRI scanner can identify DWI-FLAIR mismatch in acute ischemic stroke. METHODS: Eligible patients with a diagnosis of acute ischemic stroke underwent LF-MRI acquisition on a 0.064-T scanner within 24 h of last known well. Qualitative and quantitative metrics were evaluated. Two trained assessors determined the visibility of stroke lesions on LF-FLAIR. An image coregistration pipeline was developed, and the LF-FLAIR signal intensity ratio (SIR) was derived. RESULTS: The study included 71 patients aged 71 ± 14 years and a National Institutes of Health Stroke Scale of 6 (interquartile range 3-14). The interobserver agreement for identifying visible FLAIR hyperintensities was high (κ = 0.85, 95% CI 0.70-0.99). Visual DWI-FLAIR mismatch had a 60% sensitivity and 82% specificity for stroke patients <4.5 h, with a negative predictive value of 93%. LF-FLAIR SIR had a mean value of 1.18 ± 0.18 <4.5 h, 1.24 ± 0.39 4.5-6 h, and 1.40 ± 0.23 >6 h of stroke onset. The optimal cut-point for LF-FLAIR SIR was 1.15, with 85% sensitivity and 70% specificity. A cut-point of 6.6 h was established for a FLAIR SIR <1.15, with an 89% sensitivity and 62% specificity. INTERPRETATION: A 0.064-T portable LF-MRI can identify DWI-FLAIR mismatch among patients with acute ischemic stroke. Future research is needed to prospectively validate thresholds and evaluate a role of LF-MRI in guiding thrombolysis among stroke patients with uncertain time of onset. ANN NEUROL 2024.

Twenty Years of Get With The Guidelines-Stroke: Celebrating Past Successes, Lessons Learned, and Future Challenges.

The Get With The Guidelines-Stroke program which, began 20 years ago, is one of the largest and most important nationally representative disease registries in the United States. Its importance to the stroke community can be gauged by its sustained growth and widespread dissemination of findings that demonstrate sustained increases in both the quality of care and patient outcomes over time. The objectives of this narrative review are to provide a brief history of Get With The Guidelines-Stroke, summarize its major successes and impact, and highlight lessons learned. Looking to the next 20 years, we discuss potential challenges and opportunities for the program.

National- and State-Level Trends in Medicare Hospice Beneficiaries for Stroke During 2013 to 2019 in the United States.

BACKGROUND: Stroke is the fifth leading cause of death in the United States, one of the leading contributors to Medicare cost, including through Medicare hospice benefits, and the rate of stroke mortality has been increasing since 2013. We hypothesized that hospice utilization among Medicare beneficiaries with stroke has increased over time and that the increase is associated with trends in stroke death rate. METHODS: Using Medicare Part A claims data and Centers for Disease Control mortality data at a national and state level from 2013 to 2019, we report the proportion and count of Medicare hospice beneficiaries with stroke as well as the stroke death rate (per 100 000) in Medicare-eligible individuals aged ≥65 years. RESULTS: From 2013 to 2019, the number of Medicare hospice beneficiaries with stroke as their primary diagnosis increased 104.1% from 78 812 to 160 884. The number of stroke deaths in the United States in individuals aged ≥65 years also increased from 109 602 in 2013 to 129 193 in 2019 (17.9% increase). In 2013, stroke was the sixth most common primary diagnosis for Medicare hospice, while in 2019 it was the third most common, surpassed only by cancer and dementia. The correlation between the change from 2013 to 2019 in state-level Medicare hospice for stroke and stroke death rate for Medicare-eligible adults was significant (Spearman ρ=0.5; P<0.001). In a mixed-effects model, the variance in the state-level proportion of Medicare hospice for stroke explained by the state-level stroke death rate was 48.2%. CONCLUSIONS: From 2013 to 2019, the number of Medicare hospice beneficiaries with a primary diagnosis of stroke more than doubled and stroke jumped from the sixth most common indication for hospice to the third most common. While increases in stroke mortality in the Medicare-eligible population accounts for some of the increase of Medicare hospice beneficiaries, over half the variance remains unexplained and requires additional research.

Association Between Hematoma Volume and Risk of Subsequent Ischemic Stroke: A MISTIE III and ATACH-2 Analysis.

BACKGROUND: Nontraumatic intracerebral hemorrhage (ICH) is independently associated with a long-term increased risk of major arterial ischemic events. While the relationship between ICH location and ischemic risk has been studied, whether hematoma volume influences this risk is poorly understood. METHODS: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) trials. The exposure was hematoma volume, treated as a continuous measure in the primary analysis, and dichotomized by the median in the secondary analyses. The outcome was a symptomatic, clinically overt ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. RESULTS: Of 1470 patients with ICH, the mean age was 61.7 (SD, 12.8) years, and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (interquartile range, 7.2-35.7). During a median follow-up of 107 days (interquartile range, 91-140), a total of 30 ischemic strokes occurred, of which 22 were in patients with a median ICH volume of ≥17.3 mL and a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with a median ICH volume <17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). In primary analyses using adjusted Cox regression models, ICH volume was associated with an increased risk of ischemic stroke (hazard ratio, 1.02 per mL increase [95% CI, 1.01-1.04]). In secondary analyses, ICH volume of ≥17.3 mL was associated with an increased risk of ischemic stroke (hazard ratio, 2.5 [95% CI, 1.1-7.2]), compared with those with an ICH volume <17.3 mL. CONCLUSIONS: In a heterogeneous cohort of patients with ICH, initial hematoma volume was associated with a heightened short-term risk of ischemic stroke.

Mapping the Ecological Terrain of Stroke Prehospital Delay: A Nationwide Registry Study.

BACKGROUND: Delays in hospital presentation limit access to acute stroke treatments. While prior research has focused on patient-level factors, broader ecological and social determinants have not been well studied. We aimed to create a geospatial map of prehospital delay and examine the role of community-level social vulnerability. METHODS: We studied patients with ischemic stroke who arrived by emergency medical services in 2015 to 2017 from the American Heart Association Get With The Guidelines-Stroke registry. The primary outcome was time to hospital arrival after stroke (in minutes), beginning at last known well in most cases. Using Geographic Information System mapping, we displayed the geography of delay. We then used Cox proportional hazard models to study the relationship between community-level factors and arrival time (adjusted hazard ratios [aHR] <1.0 indicate delay). The primary exposure was the social vulnerability index (SVI), a metric of social vulnerability for every ZIP Code Tabulation Area ranging from 0.0 to 1.0. RESULTS: Of 750 336 patients, 149 145 met inclusion criteria. The mean age was 73 years, and 51% were female. The median time to hospital arrival was 140 minutes (Q1: 60 minutes, Q3: 458 minutes). The geospatial map revealed that many zones of delay overlapped with socially vulnerable areas (https://harvard-cga.maps.arcgis.com/apps/webappviewer/index.html?id=08f6e885c71b457f83cefc71013bcaa7). Cox models (aHR, 95% CI) confirmed that higher SVI, including quartiles 3 (aHR, 0.96 [95% CI, 0.93-0.98]) and 4 (aHR, 0.93 [95% CI, 0.91-0.95]), was associated with delay. Patients from SVI quartile 4 neighborhoods arrived 15.6 minutes [15-16.2] slower than patients from SVI quartile 1. Specific SVI themes associated with delay were a community's socioeconomic status (aHR, 0.80 [95% CI, 0.74-0.85]) and housing type and transportation (aHR, 0.89 [95% CI, 0.84-0.94]). CONCLUSIONS: This map of acute stroke presentation times shows areas with a high incidence of delay. Increased social vulnerability characterizes these areas. Such places should be systematically targeted to improve population-level stroke presentation times.

Code ICH: A Call to Action.

Intracerebral hemorrhage is the most serious type of stroke, leading to high rates of severe disability and mortality. Hematoma expansion is an independent predictor of poor functional outcome and is a compelling target for intervention. For decades, randomized trials aimed at decreasing hematoma expansion through single interventions have failed to meet their primary outcomes of statistically significant improvement in neurological outcomes. A wide range of evidence suggests that ultra-early bundled care, with multiple simultaneous interventions in the acute phase, offers the best hope of limiting hematoma expansion and improving functional recovery. Patients with intracerebral hemorrhage who fail to receive early aggressive care have worse outcomes, suggesting that an important treatment opportunity exists. This consensus statement puts forth a call to action to establish a protocol for Code ICH, similar to current strategies used for the management of acute ischemic stroke, through which early intervention, bundled care, and time-based metrics have substantially improved neurological outcomes. Based on current evidence, we advocate for the widespread adoption of an early bundle of care for patients with intracerebral hemorrhage focused on time-based metrics for blood pressure control and emergency reversal of anticoagulation, with the goal of optimizing the benefit of these already widely used interventions. We hope Code ICH will endure as a structural platform for continued innovation, standardization of best practices, and ongoing quality improvement for years to come.

Effect of Alteplase on Ischemic Stroke Mortality Is Dependent on Stroke Severity.

OBJECTIVE: Although intravenous alteplase (IV-tPA) has a beneficial effect on functional outcome after ischemic stroke (IS), prior studies of IV-tPA's impact on post-stroke mortality did not have sufficient representation of more severe stroke. METHODS: We determined if the interaction between the baseline National Institutes of Health (NIH) Stroke Scale (NIHSS) and IV-tPA modified the risk of mortality after IS in two cohorts: (1) National Inpatient Sample 2016-2020, and (2) a harmonized cohort of IS patients from the NINDS IV-tPA, ALIAS part 2, SHINE, FAST-MAG, IMS-III, POINT, and DEFUSE 3 trials. We fit logistic regression models to the outcome of in-hospital mortality (National Inpatient Sample [NIS] cohort) or mortality within 90 days (harmonized cohort), adjusted for baseline variables. RESULTS: We included 198,668 patients in the NIS cohort, of which 14.0% received IV-tPA and 3.4% died in hospital. We included 7,138 patients in the harmonized cohort, of which 33.2% received IV-tPA and 9.4% died by 90 days. Mortality in the NIS cohort was associated with older age, female sex, non-Hispanic white race, atrial fibrillation, and higher NIHSS. In the harmonized cohort, mortality was associated with older age, diabetes, atrial fibrillation, and higher NIHSS. In both cohorts, the interaction between NIHSS and IV-tPA was significant. In the NIS cohort, the separation became significant at NIHSS 15 and in the harmonized cohort at NIHSS 23, at which point, IV-tPA began to have a significant benefit for both in-hospital and 90-day mortality, respectively. INTERPRETATION: IV-tPA is associated with a reduction in both in-hospital and 90-day mortality for patients with more severe IS. ANN NEUROL 2023;93:1106-1116.

Intensive Blood Pressure Reduction is Associated with Reduced Hematoma Growth in Fast Bleeding Intracerebral Hemorrhage.

OBJECTIVE: Patients with spontaneous intracerebral hemorrhage (ICH) at the highest risk of hematoma growth are those with the most potential to benefit from anti-expansion treatment. Large clinical trials have not definitively shown a clear benefit of blood pressure (BP) reduction. We aim to determine whether intensive blood pressure reduction could benefit patients with fast bleeding ICH. METHODS: An exploratory analysis of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) randomized controlled trial was performed. In order to capture not just early bleeding (even if a small amount), but the rate of bleeding (ml/hour), we restricted the study to "Fast bleeding ICH," defined as an ICH volume/onset to computed tomography (CT) time >5 ml/hr. Hematoma growth, as defined as an increase of hematoma volume > 33% between baseline and 24 hours. RESULTS: A total of 940 patients were included (mean age = 62.1 years, 61.5% men), of whom 214 (22.8%) experienced hematoma expansion. Of these, 567 (60.3%) met the definition of "fast bleeding" with baseline ICH volume/time to presentation of at least 5 ml/hr. Intensive BP reduction was associated with a significantly lower rate of hematoma growth in fast bleeding patients (20.6% vs 31.0%, p = 0.005). In a subgroup of 266 (46.9%) fast-bleeding patients who received treatment within 2 hours after symptom onset, intensive BP lowering was associated with improved functional independence (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.06-3.69, p = 0.031). INTERPRETATION: Our results suggest that early use of intensive BP reduction may reduce hematoma growth and improve outcome in fast bleeding patients. ANN NEUROL 2023.

Cost-Effectiveness of CT, CTA, MRI, and Specialized MRI for Evaluation of Patients Presenting to the Emergency Department With Dizziness.

BACKGROUND. Underlying stroke is often misdiagnosed in patients presenting with dizziness. Although such patients are usually ineligible for acute stroke treatment, accurate diagnosis may still improve outcomes through selection of patients for secondary prevention measures. OBJECTIVE. The purpose of our study was to investigate the cost-effectiveness of differing neuroimaging approaches in the evaluation of patients presenting to the emergency department (ED) with dizziness who are not candidates for acute intervention. METHODS. A Markov decision-analytic model was constructed from a health care system perspective for the evaluation of a patient presenting to the ED with dizziness. Four diagnostic strategies were compared: noncontrast head CT, head and neck CTA, conventional brain MRI, and specialized brain MRI (including multiplanar high-resolution DWI). Differing long-term costs and outcomes related to stroke detection and secondary prevention measures were compared. Cost-effectiveness was calculated in terms of lifetime expenditures in 2022 U.S. dollars for each quality-adjusted life year (QALY); deterministic and probabilistic sensitivity analyses were performed. RESULTS. Specialized MRI resulted in the highest QALYs and was the most cost-effective strategy with US$13,477 greater cost and 0.48 greater QALYs compared with noncontrast head CT. Conventional MRI had the next-highest health benefit, although was dominated by extension with incremental cost of US$6757 and 0.25 QALY; CTA was also dominated by extension, with incremental cost of US$3952 for 0.13 QALY. Non-contrast CT alone had the lowest utility among the four imaging choices. In the deterministic sensitivity analyses, specialized MRI remained the most cost-effective strategy. Conventional MRI was more cost-effective than CTA across a wide range of model parameters, with incremental cost-effectiveness remaining less than US$30,000/QALY. Probabilistic sensitivity analysis yielded similar results as found in the base-case analysis, with specialized MRI being more cost-effective than conventional MRI, which in turn was more cost-effective than CTA. CONCLUSION. The use of MRI in patients presenting to the ED with dizziness improves stroke detection and selection for subsequent preventive measures. MRI-based evaluation leads to lower long-term costs and higher cumulative QALYs. CLINICAL IMPACT. MRI, incorporating specialized protocols when available, is the preferred approach for evaluation of patients presenting to the ED with dizziness, to establish a stroke diagnosis and to select patients for secondary prevention measures.

Trends in American Indian/Alaskan native self-reported stroke prevalence and associated modifiable risk factors in the United States from 2011-2021.

BACKGROUND: Stroke prevalence varies by race/ethnicity, as do the risk factors that elevate the risk of stroke. Prior analyses have suggested that American Indian/Alaskan Natives (AI/AN) have higher rates of stroke and vascular risk factors. METHODS: We included biyearly data from the 2011-2021 Behavioral Risk Factor Surveillance System (BRFSS) surveys of adults (age ≥18) in the United States. We describe survey-weighted prevalence of stroke per self-report by race and ethnicity. In patients with self-reported stroke (SRS), we also describe the prevalence of modifiable vascular risk factors. RESULTS: The weighted number of U.S. participants represented in BRFSS surveys increased from 237,486,646 in 2011 to 245,350,089 in 2021. SRS prevalence increased from 2.9% in 2011 to 3.3% in 2021 (p<0.001). Amongst all race/ethnicity groups, the prevalence of stroke was highest in AI/AN at 5.4% and 5.6% in 2011 and 2021, compared to 3.0% and 3.4% for White adults (p<0.001). AI/AN with SRS were also the most likely to have four or more vascular risk factors in both 2011 and 2021 at 23.9% and 26.4% compared to 18.2% and 19.6% in White adults (p<0.001). CONCLUSION: From 2011-2021 in the United States, AI/AN consistently had the highest prevalence of self-reported stroke and highest overall burden of modifiable vascular risk factors. This persistent health disparity leaves AI/AN more susceptible to both incident and recurrent stroke.

Precision Medicine in Neurocritical Care for Cerebrovascular Disease Cases.

Scientific advances have informed many aspects of acute stroke care but have also highlighted the complexity and heterogeneity of cerebrovascular diseases. While practice guidelines are essential in supporting the clinical decision-making process, they may not capture the nuances of individual cases. Personalized stroke care in ICU has traditionally relied on integrating clinical examinations, neuroimaging studies, and physiologic monitoring to develop a treatment plan tailored to the individual patient. However, to realize the potential of precision medicine in stroke, we need advances and evidence in several critical areas, including data capture, clinical phenotyping, serum biomarker development, neuromonitoring, and physiology-based treatment targets. Mathematical tools are being developed to analyze the multitude of data and provide clinicians with real-time information and personalized treatment targets for the critical care management of patients with cerebrovascular diseases. This review summarizes research advances in these areas and outlines principles for translating precision medicine into clinical practice.

Racial and Ethnic Differences in the Risk of Ischemic Stroke After Nontraumatic Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with an increased risk of ischemic stroke. Whether there are racial and ethnic disparities in the risk of ischemic stroke after ICH is poorly understood. We therefore aimed to test the hypothesis that non-Hispanic Black and Hispanic ICH patients have a higher risk of ischemic stroke compared with non-Hispanic White ICH patients. METHODS: We performed a retrospective cohort study using the Healthcare Cost and Utilization Project (HCUP) on all hospitalizations at all nonfederal hospitals in Florida from 2005 to 2018 and New York from 2006 to 2016. Race and ethnicity were coded as a single variable in HCUP. We included patients with an ICH, and without a prior or concomitant diagnosis of ischemic stroke, ascertained using validated International Classification of Diseases-Clinical Modification-9 and 10 diagnosis codes. Using Cox proportional hazard models, we studied the relationship between race and risk of ischemic stroke starting from the time of discharge from ICH hospitalization, after adjustment of demographics and vascular comorbidities. RESULTS: We included 91 342 patients with ICH-62% non-Hispanic White, 18% non-Hispanic Black, and 12% Hispanic patients. Non-Hispanic Black and Hispanic patients were younger and had a higher prevalence of cardiovascular comorbidities; however, atrial fibrillation was more prevalent among non-Hispanic White patients. During a median follow-up period of 4.4 years (interquartile range, 1.5-8.1), an incident ischemic stroke occurred in 3377 (6%) non-Hispanic White, 1323 (8%) non-Hispanic Black, and 844 (8%) Hispanic patients. In adjusted Cox models, the risk of an ischemic stroke was significantly higher among non-Hispanic Black patients (hazard ratio, 1.6 [95% CI, 1.5-1.8]) and Hispanic patients (hazard ratio, 1.4 [95% CI, 1.3-1.5]), compared with non-Hispanic White patients. Similar results were obtained in sensitivity analyses when using death as a competing risk and after excluding patients with atrial fibrillation and valvular heart disease. CONCLUSIONS: In a large heterogeneous cohort of patients with ICH, we found that non-Hispanic Black and Hispanic patients had a significantly higher risk of ischemic stroke compared with non-Hispanic White patients.

Effect of COVID-19 on Acute Ischemic Stroke Severity and Mortality in 2020: Results From the 2020 National Inpatient Sample.

BACKGROUND: There is a paucity of nationally representative data regarding the impact of COVID-19 on acute ischemic stroke (AIS) outcome. METHODS: We created a cross-sectional cohort of nationally weighted National Inpatient Sample nonelective hospital discharges aged ≥18 years with a diagnosis of ischemic stroke from 2016 to 2020. The outcome was in-hospital mortality and exposure was COVID-19 status. To understand the effect of COVID-19 on AIS severity, we report National Institutes of Health Stroke Scale by exposure status. In a final analysis, we used a nationally weighted logistic regression and marginal effects to compare April to December 2020 to the same period in 2019 to understand how the pandemic modified the effect of race and ethnicity and median household income on in-hospital AIS mortality. RESULTS: We observed significantly higher AIS mortality in 2020 than prior years (2020 versus 2016-19, 7.3% versus 6.3%, P<0.001) and higher National Institutes of Health Stroke Scale in those with COVID-19 than those without (mean: 9.7±9.1 versus 6.6±7.4, P<0.001), but patients with AIS without COVID in 2020 had only marginally higher mortality (2020 versus 2016-2019, 6.6% versus 6.3%, P=0.001). Comparing April to December 2020 to 2019, the adjusted risk of in-hospital AIS mortality was most notably increased in Hispanics (2020 versus 2019: 9.2% versus 5.8%, P<0.001) and the lowest quartile of income (2020 versus 2019: 8.0% versus 6.0%, P<0.001). CONCLUSIONS: In-hospital stroke mortality increased in 2020 in the United States because of comorbid AIS and COVID-19, which had higher stroke severity. The increase in AIS mortality during April-December 2020 was significantly more pronounced in Hispanics and those in the lowest quartile of household income.

Change in Smoking Behavior and Outcome After Ischemic Stroke: Post-Hoc Analysis of the SPS3 Trial.

BACKGROUND: Cigarette smoking is a known risk factor for cardiovascular disease, including ischemic stroke. The literature regarding the rate of persistent smoking after acute ischemic stroke and its effect on subsequent cardiovascular events is scarce. With this study, we aimed to report the rate of persistent smoking after ischemic stroke and the association between smoking status and major cardiovascular outcomes. METHODS: This is a post-hoc analysis of the SPS3 trial (Secondary Prevention of Small Subcortical Strokes). Patients were divided into 4 groups based on smoking status at trial enrollment: (1) never smokers, (2) former smokers, (3) smokers who quit at 3 months, and (4) persistent smokers. The primary outcome is a major adverse cardiovascular events composite of stroke (ischemic and hemorrhagic), myocardial infarction, and mortality. Outcomes were adjudicated after month 3 of enrollment until an outcome event or the end of study follow-up. RESULTS: A total of 2874 patients were included in the study. Of the total cohort, 570 patients (20%) were smokers at enrollment, of whom 408 (71.5%) patients continued to smoke and 162 (28.4%) quit smoking by 3 months. The major adverse cardiovascular events outcome occurred in 18.4%, 12.4%, 16.2%, and 14.4%, respectively, in persistent smokers, smokers who quit, prior smokers, and never smokers. In a model adjusted for age, sex, race, ethnicity, education, employment status, history of hypertension, diabetes, hyperlipidemia, myocardial infarction, and intensive blood pressure randomization arm, the risk of major adverse cardiovascular events, and death were higher in the persistent smokers compared with never smokers (HR for major adverse cardiovascular events: 1.56 [95% CI, 1.16-2.09]; HR for death: 2.0 [95% CI, 2.18-3.12]). The risk of stroke, and MI did not differ according to smoking status Conclusions: Compared with never smoking, persistent smoking after acute ischemic stroke was associated with an increased risk of cardiovascular events and death. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00059306.

Baseline Cardiovascular Risk Factor Control in Patients With Type 2 Diabetes and Coronary Disease Versus Stroke: Secondary Analysis of Cardiovascular Outcome Trials.

BACKGROUND: Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD). METHODS: Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models. RESULTS: The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67-2.51), EMPA-REG OUTCOME, 2.50 (2.10-2.99), and CAROLINA, 1.63 (1.21-2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13-1.87); EMPA-REG OUTCOME, 1.62 (1.25-2.08); and CAROLINA, 1.16 (0.74-1.83). CONCLUSIONS: In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532.

Antithrombotic and Statin Prescription After Intracerebral Hemorrhage in the Get With The Guidelines-Stroke Registry.

BACKGROUND: Survivors of intracerebral hemorrhage (ICH) face an increased risk of ischemic cardiovascular events. Current ICH guidelines do not provide definitive recommendations regarding the use of antithrombotic and statin therapies. We, therefore, sought to study practice patterns and factors associated with the use of such medications after ICH. METHODS: This was a cross-sectional study of patients with ICH in the Get With The Guidelines-Stroke registry, between 2011 and 2021. Patients transferred to another hospital, those who died during hospitalization, and those with missing information on discharge medications were excluded. The study exposure was the proportion of patients who were prescribed antithrombotic or statin medications. We first ascertained the proportion of patients prescribed antithrombotic and lipid-lowering medications at discharge overall and across strata defined by pre-ICH use and history of previous ischemic vascular disease or atrial fibrillation. We then studied factors associated with the discharge prescription of these medications after ICH, using multiple logistic regressions. RESULTS: In the final cohort, 50 416 (10.4%) of 486 586 patients with ICH were prescribed antiplatelet medications, 173 322 (35.1%) of 493 491 patients with ICH were prescribed statins, and 27 085 (5.4%) of 486 585 patients with ICH were prescribed anticoagulation therapy at discharge. The proportion of patients with antiplatelet therapy was 16.6% with pre-ICH use and 15.6% in those with previous ischemic vascular disease. Statins were prescribed to 41.1% and 43.7% of patients on previous lipid-lowering therapy and ischemic vascular disease, respectively. Anticoagulation therapy was restarted in 11.1% of patients. In logistic regression analysis, factors associated with higher use of antithrombotic or statin therapies after ICH were younger age, male sex, pre-ICH medication use, previous ischemic vascular disease, atrial fibrillation, lower admission National Institutes of Health Stroke Scale, longer length of stay, and favorable discharge outcome. CONCLUSIONS: Few patients with ICH are prescribed antithrombotic or statin therapies at hospital discharge. Given the emerging association between ICH and future major cardiovascular events, trials examining the net benefit of antiplatelet and lipid-lowering therapy after ICH are warranted.

Higher Hospital Frailty Risk Score Is Associated With Increased Risk of Stroke: Observational and Genetic Analyses.

BACKGROUND: Frailty is a prevalent state associated with several aging-related traits and conditions. The relationship between frailty and stroke remains understudied. Here we aim to investigate whether the hospital frailty risk score (HFRS) is associated with the risk of stroke and determine whether a significant association between genetically determined frailty and stroke exists. DESIGN: Observational study using data from All of Us research program and Mendelian Randomization analyses. METHODS: Participants from All of Us with available electronic health records were selected for analysis. All of Us began national enrollment in 2018 and is expected to continue for at least 10 years. All of Us is recruiting members of groups that have traditionally been underrepresented in research. All participants provided informed consent at the time of enrollment, and the date of consent was recorded for each participant. Incident stroke was defined as stroke event happening on or after the date of consent to the All of Us study HFRS was measured with a 3-year look-back period before the date of consent for stroke risk. The HFRS was stratified into 4 categories: no-frailty (HFRS=0), low (HFRS ≥1 and <5), intermediate (≥5 and <15), and high (HFRS ≥15). Last, we implemented Mendelian Randomization analyses to evaluate whether genetically determined frailty is associated with stroke risk. RESULTS: Two hundred fifty-three thousand two hundred twenty-six participants were at risk of stroke. In multivariable analyses, frailty status was significantly associated with risk of any (ischemic or hemorrhagic) stroke following a dose-response way: not-frail versus low HFRS (HR, 4.9 [CI, 3.5-6.8]; P<0.001), not-frail versus intermediate HFRS (HR, 11.4 [CI, 8.3-15.7]; P<0.001) and not-frail versus high HFRS (HR, 42.8 [CI, 31.2-58.6]; P<0.001). We found similar associations when evaluating ischemic and hemorrhagic stroke separately (P value for all comparisons <0.05). Mendelian Randomization confirmed this association by indicating that genetically determined frailty was independently associated with risk of any stroke (OR, 1.45 [95% CI, 1.15-1.84]; P=0.002). CONCLUSIONS: Frailty, based on the HFRS was associated with higher risk of any stroke. Mendelian Randomization analyses confirmed this association providing evidence to support a causal relationship.

Priorities for Advancements in Neuroimaging in the Diagnostic Workup of Acute Stroke.

STAIR XII (12th Stroke Treatment Academy Industry Roundtable) included a workshop to discuss the priorities for advancements in neuroimaging in the diagnostic workup of acute ischemic stroke. The workshop brought together representatives from academia, industry, and government. The participants identified 10 critical areas of priority for the advancement of acute stroke imaging. These include enhancing imaging capabilities at primary and comprehensive stroke centers, refining the analysis and characterization of clots, establishing imaging criteria that can predict the response to reperfusion, optimizing the Thrombolysis in Cerebral Infarction scale, predicting first-pass reperfusion outcomes, improving imaging techniques post-reperfusion therapy, detecting early ischemia on noncontrast computed tomography, enhancing cone beam computed tomography, advancing mobile stroke units, and leveraging high-resolution vessel wall imaging to gain deeper insights into pathology. Imaging in acute ischemic stroke treatment has advanced significantly, but important challenges remain that need to be addressed. A combined effort from academic investigators, industry, and regulators is needed to improve imaging technologies and, ultimately, patient outcomes.